1. Field of the Invention
This invention relates to pharmaceutical combinations and methods useful to enhance the activity of glucagon-like peptide 2 (GLP-2) in order to treat or inhibit a variety of medical conditions, disorders and diseases. More particularly, the invention relates to pharmaceutical combinations that modulate activities of glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2), for instance to suppress appetite and thereby reduce food intake, for example to treat subjects suffering from obesity, and to enhance gut growth and function to treat gastrointestinal conditions.
2. Background to the Invention
The glucagon-like peptides are liberated in the gut and central nervous system via tissue-specific posttranslational processing of a common proglucagon precursor (1). GLP-1 and GLP-2 are secreted from the gut following nutrient ingestion and regulate nutrient absorption and energy homeostasis (2,3). The actions of glucagon-like peptide-1 (GLP-1) include regulation of gastric emptying, gastric acid secretion, inhibition of food intake and glucagon secretion, and stimulation of glucose-dependent insulin secretion and insulin biosynthesis (2-5). GLP-1 also promotes expansion of islet mass via stimulation of  cell proliferation and induction of islet neogenesis via increased ductal pdx-1 expression (6,7). Taken together, these actions of GLP-1 maintain euglycemia, hence enhancing GLP-1 action may represent a useful strategy for the treatment of diabetes mellitus.
Glucagon-like peptide-2 (GLP-2) exhibits trophic properties in the small and large bowel characterized by expansion of the mucosal epithelium predominantly via stimulation of crypt cell proliferation (8-10). GLP-2 also regulates gastric motility, and gastric acid release, intestinal permeability and intestinal hexose transport, actions independent of its effects on epithelial growth (11-14). The intestinotrophic and cytoprotective properties of GLP-2 have been evaluated in the setting of acute intestinal injury, where GLP-2 administration inhibits apoptosis and reduces the severity of mucosal damage in both the small and large intestine (15-18).
In the central nervous system, the glucagon-like peptides are synthesized predominantly in the caudal brainstem and to a lesser extent, in the hypothalamus (19-21). The GLP-1 receptor is expressed more widely throughout the CNS (22,23), and GLP-1 has been shown to regulate appetite, hypothalamic pituitary function, and the central response to aversive stimulation (24-29). Peripheral administration of GLP-1 or the lizard GLP-1 analogue exendin-4 also reduces food intake and body weight (30,31) suggesting that gut-derived GLP-1 provides signals that influence feeding behavior either directly to the brain, or indirectly, likely via vagal afferents.
In contrast to the increasing number of studies describing CNS actions of GLP-1, much less is known about the potential function(s) of GLP-2 in the brain. Experiments using rat hypothalamic and pituitary membranes demonstrated GLP-2-mediated activation of adenylate cyclase (32). Consistent with these findings, the actions of GLP-2 were subsequently shown to be transduced in a cAMP-dependent manner via a recently cloned GLP-2 receptor (GLP-2R) isolated from hypothalamic and intestinal cDNA libraries (33). The GLP-2R is expressed in a highly tissue-specific manner predominantly in gut endocrine cells, and in the brain (33,34). In comparison with GLP-1, little is known about either the expression or function of the GLP-2R in different regions of the CNS.
Both GLP-1 and GLP-2-immunoreactive fiber tracts project from the brainstem to multiple CNS regions, including the hypothalamus, thalamus, cortex, and pituitary (21,35). Intracerebroventricular (icv) infusion of GLP-2 in rats inhibited food intake (35), (and see WO97/31943 published 4 Sep. 1997), similar to results obtained following icv infusion of GLP-1 (24,36). Unexpectedly, the anorectic effects of GLP-2 in rats were completely inhibited by the GLP-1 receptor antagonist exendin (9-39) (35). These findings implied that CNS GLP-2 may exert its effects via the GLP-1 receptor to inhibit food intake, or alternatively, exendin (9-39) may also function as a CNS GLP-2R antagonist.
It is an object of the present invention to provide a method of medical treatment useful to enhance the medically beneficial effects of GLP-2.
It is another object of the present invention to provide a pharmaceutical combination useful for providing an enhanced GLP-2 effect in subjects for which GLP-2 therapy is indicated.
It is another object of the present invention to provide a method by which the medically beneficial effect of GLP-2 is enhanced.
It is a particular object of the present invention to provide methods of medical treatment, and pharmaceutical compositions therefor, that are useful to regulate appetite, for treatment particularly of subjects suffering from eating disorders and related conditions such as obesity.